Menthol-Induced Ca²⁺Release from Presynaptic Ca²⁺Stores Potentiates Sensory Synaptic Transmission

Abstract

Menthol and many of its derivatives produce profound sensory and mental effects. The receptor for menthol has been cloned and named cold-and menthol-sensitive receptor-1 (CMR1) or transient receptor potential channel M8 (TRPM8) receptor. Using a dorsal root ganglion (DRG) and dorsal horn (DH) coculture system as a model for the first sensory synapse in the CNS, we studied menthol effects on sensory synaptic transmission and the underlying mechanisms. We found that menthol increased the frequency of miniature EPSCs (mEPSCs). The effects persisted under an extracellular Ca 2ϩ -free condition but were abolished by intracellular BAPTA and pretreatment with thapsigargin. Menthol-induced increases of mEPSC frequency were blocked by 2-aminoethoxydiphenylborane (2-APB) but not affected by the phospholipase C inhibitor U73122 or by the cADP receptor inhibitor 8-bromo-cADPR (8Br-cADPR). , resulting in a facilitation of glutamate release and a modulation of neuronal transmission at sensory synapses. Expression of TRPM8 receptor on presynaptic Ca 2ϩ stores, a novel localization for this ligand-gated ion channel, is also strongly suggested.

Transient receptor potential melastatin 8 channel involvement in the regulation of vascular tone

“…Many recent studies (6,8,34,36) have implicated the TRPM8 channel as a regulator of intracellular calcium. Increased intracellular Ca 2ϩ concentrations associated with channel activation (38) would be expected to cause contraction.…”

Regulation of Piezo2 Mechanotransduction by Static Plasma Membrane Tension in Primary Afferent Neurons

“…Experimental protocols were approved by the Institutional Animal Care and Use Committee at the University of Cincinnati. DRG neuron cultures were prepared as described previously (21). In brief, rats were anesthetized with isoflurane and sacrificed by decapitation.…”

Downregulation of Transient Receptor Potential Melastatin 8 by Protein Kinase C-Mediated Dephosphorylation

“…Modulation of TRPM8-mediated synaptic transmission by PKC TRPM8 and TRPV1 are also distributed in central terminals of the sensory neurons, which synapse with the dorsal horn neurons in the spinal cord (Baccei et al, 2003;Tsuzuki et al, 2004). We determined whether activation of PKC alters TRPM8-and TRPV1-mediated synaptic transmission at the first sensory synapse.…”

“…TRPM8 is activated by cold (Ͻ25°C) and agents like menthol (an active ingredient of peppermint), icilin, and eucalyptol, which induce a cool/soothing sensation (McKemy et al, 2002;Peier et al, 2002;Reid et al, 2002). Not only does TRPM8 sense temperature at the periphery, but it also mediates synaptic transmission at the first sensory synapse between dorsal root ganglion (DRG) and dorsal horn (DH) neurons in the spinal cord (Baccei et al, 2003;Tsuzuki et al, 2004). In contrast, TRPV1 is activated by heat (Ͼ42°C), protons, N-arachidonoyldopamine, anandamide, and lipoxygenase products and is involved in the detection of inflammatory thermal pain (Caterina et al, 1997;Tominaga et al, 1998;Hwang et al, 2000;Chuang et al, 2001;Julius and Basbaum, 2001;Huang et al, 2002).…”

“…In contrast, TRPV1 is activated by heat (Ͼ42°C), protons, N-arachidonoyldopamine, anandamide, and lipoxygenase products and is involved in the detection of inflammatory thermal pain (Caterina et al, 1997;Tominaga et al, 1998;Hwang et al, 2000;Chuang et al, 2001;Julius and Basbaum, 2001;Huang et al, 2002). Distribution of TRPM8 and TRPV1 in areas that are not subjected to these temperature ranges suggests a role beyond that as temperature sensors (Manzini, 1992;Zygmunt et al, 1999;Mezey et al, 2000;Birder et al, 2002;Baccei et al, 2003;Tsuzuki et al, 2004). TRPM8 (previously identified as Trp-p8) is upregulated in prostate cancer and is involved in urinary bladder function, which broadens the horizon of TRPM8 in other pathophysiological conditions (Tsavaler et al, 2001).…”